EP0962878B1 - Reflexalgorithmus zur frühen und kostengünstigen Diagnose von myokardischen Infarkten geeignet für automatisierte diagnostische Plattformen - Google Patents

Reflexalgorithmus zur frühen und kostengünstigen Diagnose von myokardischen Infarkten geeignet für automatisierte diagnostische Plattformen Download PDF

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EP0962878B1
EP0962878B1 EP99110216A EP99110216A EP0962878B1 EP 0962878 B1 EP0962878 B1 EP 0962878B1 EP 99110216 A EP99110216 A EP 99110216A EP 99110216 A EP99110216 A EP 99110216A EP 0962878 B1 EP0962878 B1 EP 0962878B1
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biochemical marker
analyzer
clinical chemistry
marker measurement
biochemical
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EP0962878A2 (de
EP0962878A3 (de
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Glenn Armstrong
Christoph Petry
Gerald Wagner
Alan Wu
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N35/00—Automatic analysis not limited to methods or materials provided for in any single one of groups G01N1/00 - G01N33/00; Handling materials therefor
    • G01N35/00584—Control arrangements for automatic analysers
    • G—PHYSICS
    • G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
    • G16H—HEALTHCARE INFORMATICS, i.e. INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR THE HANDLING OR PROCESSING OF MEDICAL OR HEALTHCARE DATA
    • G16H50/00—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics
    • G16H50/20—ICT specially adapted for medical diagnosis, medical simulation or medical data mining; ICT specially adapted for detecting, monitoring or modelling epidemics or pandemics for computer-aided diagnosis, e.g. based on medical expert systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S128/00—Surgery
    • Y10S128/92—Computer assisted medical diagnostics

Definitions

  • the present invention relates to method and system for recommending a sequence of biochemical marker measurements tests to assist in the early diagnosis of acute myocardial infarction, wherein said method is based on a reflex algorithm.
  • the algorithm of the present invention assists in the determination of the appropriate biochemical tests to be conducted on a given patient and alleviates unnecessary assays, and is well-suited for implementation on an automated diagnostic platform which integrates immunoassays and clinical chemistry assays.
  • Reflex algorithms i.e., algorithms which specify selection of subsequent tests based on results of previous tests, without the need for subjective human decision-making in selecting tests
  • TSH thyroid stimulating hormone
  • J. Ellenius et al. disclosed a computer assisted approach to diagnose acute myocardial infarctions.
  • creatine kinase isoforms, myoglobin and Troponin T were measured in short time intervals and the diagnosis was made by processing the results using a neural network.
  • Such a neural network is not performed in the manner of reflex testing and does not try to minimize the number of necessary tests. Instead, it focuses on obtaining the most accurate information as early as possible from several different tests run in very short intervals.
  • a method for detecting myocardial infarction in an individual includes performing one of a plurality of sequences of biochemical marker measurement steps prescribed by a decision tree, each of the biochemical marker measurement steps including measuring a concentration level of at least one biochemical marker of myocardial infarction in a serum, plasma or whole blood sample obtained from the individual at one of a plurality of times from admission.
  • Each sequence of the decision tree begins with a common first biochemical marker measurement step conducted on a first serum, plasma or whole blood sample obtained from the individual within a first predetermined time from admission.
  • Each of the biochemical marker measurement steps subsequent to the common first step is selectively performed based on results from a precedent biochemical marker measurement step, each sequence terminating in a respective final biochemical marker measurement step conducted on serum, plasma, or whole blood sampled from the individual at one of a plurality of different times subsequent to admission.
  • an indication of myocardial infarction is provided for the individual based on the sequence of biochemical marker measurement steps performed and on the results of the final biochemical marker measurement step.
  • an illustrative AMI detection reflex algorithm which establishes useful biochemical tests for patients with suspected myocardial infarction, begins with the step of testing myoglobin and total creatine kinase activity (total-CK) upon admission to the emergency room or within a short defined time interval after admission. Then, in accordance with the reflex algorithm, if a negative result is obtained for either of these two biochemical marker tests, the two biochemical marker tests are repeated approximately every four hours until there is a positive result, or until the test combination is run a predetermined number (e.g., four) of times.
  • a predetermined number e.g., four
  • CKMB creatine kinase MB
  • troponin I is measured for clarification.
  • sequences specified according to the decision tree end with a Troponin I test as the final test.
  • the cut-offs of the different markers used in the Reflex algorithm are not necessarily identical with the clinically-determined normal ranges and may be adjusted for optimal performance of the Reflex algorithm.
  • the Reflex algorithm is implemented on a computer system, including automated diagnostic systems, and may also be implemented as a computer program stored on a computer-readable medium.
  • the Reflex algorithm of the present invention in addition to determining the next most appropriate biochemical marker test, also serves as an Expert System by offering suggestions for clinically explaining the test results and/or recommendations for treatment and/or testing other than the specific sequence of biochemical marker tests needed to detect MI.
  • a system which includes an immunoassay analyzer, a clinical chemistry analyzer, and a processor coupled to the immunoassay analyzer and to the clinical chemistry analyzer.
  • the processor commands the immunoassay analyzer and clinical chemistry analyzer to execute measurements specified by a program executed by the processor in order to facilitate diagnosis of a pathology according to a reflex algorithm which includes at least one immunoassay and at least one clinical chemistry assay.
  • the method and apparatus of the present invention by providing a reflex algorithm for detecting AMI, facilitates unambiguous and early diagnosis of acute myocardial infarctions. Additionally, it not only aids in the determination of the appropriate biochemical tests that need to be run on a patient who presents chest pain or a suspected heart-associated condition but also, omits the execution of unnecessary assays while ensuring that all necessary combinations of laboratory results are covered.
  • the reflex algorithm of the present invention by selecting subsequent tests based upon the results of previously-run assays, automatically selects the appropriate biochemical markers for a given clinical situation, which concomitantly eliminates the need for human decision-making in selecting the tests, and minimizes the number of necessary tests that have to be run, thus leading to a faster and more reliable diagnosis of AMI. Such features are tantamount to diagnostic efficiency and cost effectiveness.
  • FIGS. 1A-1F there is shown an operational flow or state diagram for a Reflex algorithm in accordance with an embodiment of the present invention.
  • the depicted Reflex algorithm represents a decision tree, or hierarchical organization, of biochemical marker measurements, including both immunochemistry and clinical chemistry assays in which the markers have different appearance kinetics influencing their sensitivities and specificities within different time windows. More specifically, the illustrative Reflex algorithm of FIGS. 1A-1F employs myoglobin, total creatine kinase (tCK or total CK) activity, creatine kinase MB (CKMB) mass, and cardiac troponin I (cTNI) biochemical marker measurements.
  • tCK or total CK total creatine kinase activity
  • CKMB creatine kinase MB
  • cTNI cardiac troponin I
  • myoglobin has early sensitivity to myocardial infarction (about 2-3 hours post infarction), while its level returns to normal within about 24 hours, whereas total CK is elevated about 6 to 48 hours post-infarction and peaks about 18 hours after the onset of symptoms. Both myoglobin and especially total CK are relatively inexpensive, but are also non-specific to the myocardium.
  • Troponin I is very specific but appears in the circulation later, and is relatively expensive compared to myoglobin or total CK. The optimum sensitivity for Troponin occurs at about 5-48 hours post-infarction.
  • CKMB has a specificity less than that of Troponin I but greater than that of myoglobin and total CK, and has a sensitivity time window of about 5-48 hours post-infarction.
  • rectangular shapes indicate assay execution steps (i.e., one or more biochemical marker measurements), elliptical nodes identify provisional or final patient status indications depending respectively on whether or not they are followed by an additional biochemical marker measurement step (i.e., indicated by a rectangle), trapezoidal nodes indicate suggested treatments and/or follow-up procedures based on the diagnostic endpoint (i.e., the final patient status indication) and preferably also on the sequence of foregoing test results which lead to the endpoint.
  • assay execution steps i.e., one or more biochemical marker measurements
  • elliptical nodes identify provisional or final patient status indications depending respectively on whether or not they are followed by an additional biochemical marker measurement step (i.e., indicated by a rectangle)
  • trapezoidal nodes indicate suggested treatments and/or follow-up procedures based on the diagnostic endpoint (i.e., the final patient status indication) and preferably also on the sequence of foregoing test results which lead to the endpoint.
  • the elliptical nodes which are followed by another assay execution step do not represent steps which are necessarily indicated in practicing the Reflex algorithm, but are shown for clarity in describing the underlying logical structure and arrangement of the operational flow.
  • provisional indications may be provided as suggestions for clinically explaining the test results thus far obtained, and may also be associated with other suggested treatments or recommendations to the physician.
  • FIG. 1F are executed on blood drawn, in order, upon admission (e.g., within about three hours of admission), and in four hour increments subsequent to the time of the initially drawn blood upon admission (i.e., FIG. 1D and FIG. 1E corresponding to 12 hours and 16 hours post-admission, respectively).
  • FIG. 1D and FIG. 1E corresponding to 12 hours and 16 hours post-admission, respectively.
  • reference to blood, blood sample, or the like being used for a biochemical marker measurement is generically used to refer to using whole blood, serum, or plasma as appropriate for the assay conducted.
  • both myoglobin and total creatine kinase (total CK) assays are run on blood samples drawn from the patient at that time (step 100 ), which is preferably as soon as possible. Initially testing both myoglobin and total-CK is effective in detecting recent (e.g., 2-3 hours post-onset) as well as older (e.g., 5-48 hours post-onset) infarctions.
  • step 100 If in step 100 , the total CK measurement produces a positive result (indicated tcK:P; "positive" total CK meaning that total CK activity is above some threshold level), indicating the possibility of AMI (step 106 ) or the possibility of progressed AMI (i.e., late AMI, step 108 ), then in step 110 a creatine kinase MB measurement (CKMB) is performed using the first blood sample, and the percentage relative index (%RI) represented by the ratio of CKMB to total CK (using the total CK measurement for the first blood sample) is calculated.
  • CKMB creatine kinase MB measurement
  • CKMB concentration is above a threshold level (i.e., positive, indicated as CKMB:P) and %RI is above a threshold (i.e., positive, indicated as %RI:P)
  • AMI consonant with the World Health Organization definition, is indicated as the diagnosis of cardiac status for the patient (step 112 ), and preferably a follow-up CKMB measurement is suggested to the physician (step 118 ).
  • step 110 the CKMB concentration is negative and %RI is negative (i.e., CKMB:N, %RI:N), indicating a possible skeletal muscle injury causation (step 116 )
  • step 116 the flow proceeds via step 236 wherein the concentration of cardiac troponin I (cTNI) is measured for blood drawn about four hours after the first blood sample was drawn.
  • step 110 the CKMB concentration is positive and %RI is negative (i.e., CKMB:P, %RI:N), indicating a possible AMI or possible skeletal muscle injury causation (step 114 ), then cTNI is measured for the first blood sample (step 120 ).
  • step 120 cTNI If in step 120 cTNI is positive, then AMI, consonant with the World Health Organization definition, is indicated as the diagnosis of cardiac status for the patient (step 122 ), and preferably a follow-up troponin I measurement is suggested to the physician (step 126 ). Alternatively, if in step 120 cTNI is negative (i.e., TNI:N), indicating a possible skeletal muscle injury causation (step 124 ), then to further titrate the diagnosis and more specifically assess cardiac status, the flow proceeds to step 228 wherein the concentration of troponin I is measured for blood drawn about four hours after the first blood sample was drawn.
  • TNI:N indicating a possible skeletal muscle injury causation
  • FIG. 1A provides possible pathways (i.e., a pathway representing a series of biochemical marker measurement steps performed according to the Reflex method, also referred to herein as a thread or sequence) for early detection of AMI as represented by the two diagnostic endpoints indicative of AMI (i.e., steps 112 and 122 ) which result from biochemical measurements on blood drawn upon admission only and do not require further blood samples that may be needed to diagnosis cardiac status in other patients according to the Reflex method.
  • pathways i.e., a pathway representing a series of biochemical marker measurement steps performed according to the Reflex method, also referred to herein as a thread or sequence
  • both tests indicating negative results (indicated as Myo:N, tcK:N; "negative” total CK meaning that total CK activity is below some threshold level; "negative” myoglobin meaning that myoglobin blood concentration is less than some threshold level) suggests that AMI is either not present or in its very early stages (step 102 ).
  • a positive myoglobin result i.e., indicating a myoglobin blood concentration greater than a threshold level
  • negative total CK result suggests that AMI may be in its early stages (step 104 ) because, as described, the myoglobin assay has its greatest sensitivity earlier than that of the total CK assay sensitivity.
  • step 200 an additional set of myoglobin and total CK tests are run (step 200 ) on blood drawn preferably about four hours after the time that the blood was drawn for the first set of myoglobin/total CK assays.
  • steps 200-226 are directly analogous to hereinabove described steps 100-126 , and thus will not be specifically described for purposes of brevity and clarity of exposition.
  • biochemical marker measurements in steps 200-226 are preferably conducted on blood sampled about four hours after the first blood sample was drawn from the patient, steps 200-226 thus representing a measurement sequence corresponding to steps 100-126 but time delayed in order to identify, diagnose, and/or titrate delayed presentation of AMI relative to time of admission.
  • step 210 if either (i) both CKMB and %RI are negative in step 210 , or (ii) cTNI is negative in step 220 , each case indicative of possible skeletal muscle injury (steps 216 and 224 ), then to further titrate the diagnosis and more specifically assess cardiac status, the flow proceeds to step 328 wherein the concentration of troponin I (cTNI) is measured for blood drawn about eight hours after the first blood sample was drawn.
  • cTNI concentration of troponin I
  • step 200 similar to step 100 , in either case where total CK is negative (steps 202 and 204 ), myoglobin and total CK will be measured on a subsequently drawn blood sample (step 300 ), which in this case is for blood drawn preferably about eight hours after the first blood sample (i.e., about four hours after the second blood sample).
  • step 200 if in step 200 either: (i) both tests indicate negative results (i.e., Myo:N, tcK:N), suggesting that AMI is not present (step 202 ) because there was no positive change in total CK (i.e., no increase in activity beyond the threshold) and myoglobin either remained or became negative, or (ii) myoglobin is positive and total CK is negative (Myo:P, tCK:N), suggesting that the patient may be in the early stages of AMI (step 204 ) because total CK remained negative and myoglobin remained or became positive, then in step 300 myoglobin and total CK is measured for blood drawn about eight hours after the first blood sample was drawn.
  • step 228 since a cTNI measurement of the first blood sample (i.e., step 120 ) did not indicate a level sufficient to indicate AMI, cTNI is measured for blood sampled about four hours after the first blood sample was drawn in order to further titrate a diagnosis. If in step 228 cTNI is positive, then AMI, consonant with the World Health Organization definition, is indicated as the diagnosis of cardiac status for the patient (step 122 ), and preferably a follow-up troponin I measurement is suggested to the physician (step 322 ).
  • step 228 cTNI is negative (i.e., cTNI:N), indicating a possible skeletal muscle injury causation (step 124 ), then to still further differentiate a diagnosis and more specifically assess cardiac status with a statistically significant degree of certainty, the flow proceeds to step 328 wherein the concentration of troponin I is measured for blood drawn about eight hours after the first blood sample was drawn.
  • cTNI is measured for blood sampled about four hours after the first blood sample was drawn in order to further assess the cause of elevated cTNI and to differentiate a diagnosis. If in step 236 cTNI is positive, then AMI is indicated as the diagnosis of cardiac status for the patient (step 238 ), and preferably a follow-up troponin I measurement is suggested to the physician (step 242 ).
  • step 236 cTNI is negative (i.e., cTNI:N), indicating a possible skeletal muscle injury causation (step 240 ), then to still further differentiate a diagnosis and more specifically assess cardiac status with a statistically significant degree of certainty, the flow proceeds to step 328 wherein the concentration of troponin I is measured for blood drawn about eight hours after the first blood sample was drawn.
  • step 328 if cTNI is positive, then cardiac damage which is possibly but not likely AMI is indicated as the diagnosis of cardiac status for the patient (step 330 ), and preferably a follow-up troponin I measurement is suggested to the physician (step 242 ). It is noted that the degree of cardiac damage may be further indicated, as well as different suggested treatments, based on the measured troponin I level (e.g., greater than 0.9 ng/ml indicating AMI rather than unstable angina).
  • step 328 cTNI is negative (i.e., cTNI:N), still indicating a possible skeletal muscle injury causation (step 332 ), then to still further differentiate a diagnosis and more specifically assess cardiac status with a statistically significant degree of certainty, the flow proceeds to step 428 where the concentration of troponin I is measured for blood drawn about twelve hours after the first blood sample was drawn.
  • step 300 which is performed if total CK activity was negative for both the first blood sample (step 100 ) and the blood sample drawn four hours after the first blood sample (step 200 ), if myoglobin and total CK measurements both produce negative results, then it is likely that no AMI is present (step 302 ) because the total CK activity never exceeded the threshold and the myoglobin concentration either decreased below threshold or never exceeded the threshold. Accordingly, in order to further differentiate the diagnosis and more specifically assess cardiac status, in step 428 the concentration of troponin I (cTNI) is measured for blood drawn about twelve hours after the first blood sample was drawn.
  • cTNI troponin I
  • step 300 If, however, in step 300 the total CK measurement produces a positive result, indicating the possibility of AMI (step 306 ) or the possibility of progressed AMI (i.e., late AMI, step 308 ), then in step 310 a creatine kinase MB measurement (CKMB) is performed using the blood sampled at about eight hours after the first blood sample, and the percentage relative index (%RI) represented by the ratio of CKMB to total CK (using the total CK measurement for the eight-hour blood sample) is calculated.
  • CKMB creatine kinase MB measurement
  • CKMB concentration is above a threshold level (i.e., positive, indicated as CKMB:P) and %RI is above a threshold (i.e., indicated as %RI:P)
  • AMI consonant with the World Health Organization definition, is indicated as the diagnosis of cardiac status for the patient (step 312 ), and preferably a follow-up CKMB measurement is suggested to the physician (step 318 ).
  • step 310 if in step 310 the CKMB concentration is negative and %RI is negative (i.e., CKMB:N, %RI:N), indicating a possible skeletal muscle injury causation (step 316 ), then to further differentiate the diagnosis and more specifically assess cardiac status, the flow proceeds to step 428 wherein the concentration of troponin I is measured for blood drawn about twelve hours after the first blood sample was drawn. If, however, in step 310 the CKMB concentration is positive and %RI is negative (i.e., CKMB:P, %RI:N), indicating a possible AMI or possible skeletal muscle injury causation (step 314 ), then cTNI is measured for the blood sample drawn about eight hours after the first blood sample was drawn (step 320 ).
  • step 320 cTNI If in step 320 cTNI is positive, then AMI, consonant with the World Health Organization definition, is indicated as the diagnosis of cardiac status for the patient (step 322 ), and preferably a follow-up troponin I measurement is suggested to the physician (step 322 ). Alternatively, if in step 320 cTNI is negative (i.e., TNI:N), indicating a possible skeletal muscle injury causation (step 324 ), then to further differentiate the diagnosis and more specifically assess cardiac status, the flow proceeds to step 428 wherein the concentration of troponin I is measured for blood drawn about twelve hours after the first blood sample was drawn.
  • TNI:N indicating a possible skeletal muscle injury causation
  • step 428 which, as may be understood from the foregoing, will be performed as a result of any one of multiple pathways unless terminated before, if the troponin I concentration exceeds a threshold, corresponding to a positive result (i.e., TNI:P), then cardiac damage is indicated (step 432 ) as a diagnosis, and preferably certain specific follow up procedures are recommended (step 436 ) (e.g., follow up visit for troponin I measurement). It is noted that the degree of cardiac damage may be further indicated, as well as different suggested treatments, based on the measured troponin I level (e.g., greater than 0.9 ng/ml indicating AMI rather than unstable angina).
  • the troponin I measurement result is negative (i.e., cTNI:N)
  • cTNI:N the troponin I measurement result
  • no cardiac damage is indicated as the diagnosis (step 430 ), and it is recommended that the patient be treated for non-cardiac origin of chest pain (step 434 ).
  • step 300 if myoglobin is positive and total CK is negative, indicating a possible early AMI (step 304 ), then yet a further myoglobin and total CK measurement is taken, using blood sampled at about twelve hours after the first blood sample was drawn (step 400 ).
  • steps 400-426 , steps 500-526 , steps 528-534, and steps 628-636 are not described in detail because they directly correspond, in order, to the flow of steps 200-226 , steps 300-326 , steps 328-334 , and steps 428-436 with the following distinctions.
  • step 300 a positive myoglobin result and a negative tCK result are followed by a myoglobin and total CK measurement on a later drawn blood sample in step 400 (i.e., initiating the time delayed pathways represented by steps 400-426 , steps 500-526 , steps 528-534 , and steps 628-636 )
  • step 500 a positive myoglobin result and a negative total CK are followed by a cTNI measurement, since troponin I has not been elevated (i.e., at a positive level) for measurements on blood sampled every four hours through sixteen hours.
  • time delayed measurement pathways following a measurement of positive myoglobin and negative tCK in step 300 are provided to ensure the possibility of properly diagnosing AMI in the event that the elevated myoglobin on blood sampled eight hours after the first blood was drawn is due to a delayed presentation of AMI relative to time of admission (i.e., early AMI).
  • step 400 since a measurement of positive myoglobin and negative tCK in step 300 , after twelve hours, may be indicative of early AMI detection, in addition to specifying a subsequent biochemical marker measurement step (i.e., step 400 ), in accordance with the present invention, not only may this provisional indication of early AMI be noted to a physician (corresponding to noting time of AMI onset) but also a recommendation of certain treatments to mitigate further cardiac damage may also be made to the physician.
  • provisional indications i.e., indicated by elliptical shapes
  • certain recommended treatments or other clinical tests may be noted to a physician as the measurements specified by the Reflex algorithm progressively are performed before an endpoint is reached.
  • the indications and/or recommended treatments at a given point, including the endpoints, in the Reflex method may be not only dependent on the endpoint itself (i.e., characterized by at least one sequence of tests that result in the endpoint), but also further dependent on the specific pathway traversed (i.e., the specific sequence of tests performed and their results) thereto, since, as depicted, more than one pathway may lead to a common point in the flow.
  • an early diagnosis of AMI within the four hour time window may be suggestive of invasive treatment (e.g., enzymatic lysis or rescue PTCA), whereas later diagnosis of AMI (e.g., 12 hours) may be suggestive on non-invasive treatments.
  • invasive treatment e.g., enzymatic lysis or rescue PTCA
  • later diagnosis of AMI e.g., 12 hours
  • the indication and/or recommendation at step 330 preferably depends on whether it was reached via path 110 ⁇ 120 ⁇ 228 ⁇ 328 or path 200 ⁇ 210 ⁇ 328 : the former path indicating AMI as very likely because CKMB was elevated, the latter path indicating a reasonable likelihood of unstable angina because CKMB was not elevated.
  • the Reflex method provides for an Expert system for assessing and treating patients with possible cardiac damage.
  • Such an Expert system may also draw upon additional patient information, such as patient medical history, other clinical tests performed since admission, and family history, preferably stored in a database, in order to provide a diagnosis and/or a treatment recommendation.
  • FIGS. 1A-1F provides possible pathways for detection of AMI or cardiac damage without requiring that all blood samples included in the overall Reflex method be drawn. More specifically: two diagnostic endpoints are provided based only on blood drawn upon admission (i.e., steps 112 and 122 ); four diagnostic endpoints are provided based only on blood drawn upon admission and four hours later (i.e., steps 212, 222, 230, and 238 ); three diagnostic endpoints are provided based only on blood drawn upon admission, and four and eight hours later (i.e., steps 312, 322, and 330 ); four diagnostic endpoints are provided based only on blood drawn upon admission, as well as four, eight, and twelve hours later (i.e., steps 412, 422, 430, and 432 ); three diagnostic endpoints are provided based only on blood drawn upon admission, as well as four, eight, twelve, and sixteen hours later (i.e., steps 512, 522,
  • the design of such a Reflex method for detecting AMI is based on sequencing biochemical marker measurements having various sensitivity, specificity, and appearance kinetics in such a manner so as to include pathways that: (i) result in an indication of no cardiac damage with a high degree of confidence (i.e., small probability of false negative), and (ii) result in an indication of AMI without always requiring that measurements be made on blood sampled for all blood sampling times used in the Reflex method, while accounting for the possibility of various onset times of AMI relative to time of admission.
  • a high degree of confidence i.e., small probability of false negative
  • markers may be substituted for ones used in the Reflex algorithm of FIGS. 1A-1F ; for example, glycogen phosphorylase or heart-type fatty acid binding protein may be substituted for myoglobin, or Troponin T may be substituted for Troponin I.
  • alternative Reflex algorithms may be designed and implemented using any of myriad other biochemical markers having various sensitivity, specificity, appearance kinetics, and costs, including for example: myoglobin, total creatine kinase, creatine kinase MB, troponin T, troponin I, glycogen phosphorylase BB, lactate dehydrogenase, heart-type fatty acid binding protein (h-FABP), carbonic anhydrase III, actin, myosin, and creatine kinase MB isoforms.
  • biochemical markers having various sensitivity, specificity, appearance kinetics, and costs, including for example: myoglobin, total creatine kinase, creatine kinase MB, troponin T, troponin I, glycogen phosphorylase BB, lactate dehydrogenase, heart-type fatty acid binding protein (h-FABP), carbonic anhydrase III, actin, myosin, and creatine kinase MB
  • the design of such a Reflex method may also consider other factors, such as the associated monetary cost of the different biochemical marker measurements, time of blood sampling, and assay threshold levels.
  • troponin I measurements could replace CKMB measurements if cost were not a consideration; however, since troponin I is relatively expensive, CKMB measurements are implemented in various pathways (e.g., lower risk) to further differentiate a diagnosis such that a troponin I measurement may not be necessary.
  • the times at which the patient's blood is drawn are selected in accordance with the preferred times (e.g., based on time-dependent sensitivity) for the various assays, as known from established testing procedures.
  • Standard thresholds/levels may be implemented for the different assays used; however, as may be further understood below, the thresholds preferably may be adjusted to optimize diagnosis (e.g., a more conservative threshold to minimize false negatives) for a given Reflex algorithm decision tree structure.
  • the preliminary Reflex algorithm should be, if at all, modified in order to enhance classification (e.g., adding additional testing steps to certain branches of the algorithm and/or adjusting certain threshold levels, such as increasing a threshold level to avoid false negatives) and/or efficiency (e.g., eliminating certain steps of a branch in the algorithm and/or adjusting certain threshold levels).
  • modified in order to enhance classification e.g., adding additional testing steps to certain branches of the algorithm and/or adjusting certain threshold levels, such as increasing a threshold level to avoid false negatives
  • efficiency e.g., eliminating certain steps of a branch in the algorithm and/or adjusting certain threshold levels.
  • an AMI Reflex method such as that illustrated in FIGS. 1A-1F is preferably implemented programmatically in a processing system. It is appreciated that there are myriad processing system arrangements as well as programming paradigms for implementing the AMI Reflex method. For example, in a relatively simple arrangement, FIG.
  • FIG. 2 illustrates a conventional digital computer system 60 , comprising processing unit 66 coupled to memory 64 (e.g., RAM), another computer-readable medium 65 (e.g., flash memory, magnetic hard-drive, CD-ROM, etc.), an input device 68 (e.g., a keyboard and/or mouse and/or digital data input port), and output devices such as display 70 and printer 72, and wherein computer system 60 implements an AMI Reflex algorithm (e.g., the algorithm depicted in FIGS. 1A-1F ) by stored-program execution.
  • memory 64 e.g., RAM
  • another computer-readable medium 65 e.g., flash memory, magnetic hard-drive, CD-ROM, etc.
  • input device 68 e.g., a keyboard and/or mouse and/or digital data input port
  • output devices such as display 70 and printer 72
  • computer system 60 implements an AMI Reflex algorithm (e.g., the algorithm depicted in FIGS. 1A-1F ) by stored-program execution
  • input device 68 implemented as a keyboard may be used by an operator to input results from one or more biochemical marker measurements, the input results then undergoing processing by program control of processing unit 66 in accordance with the AMI Reflex method, and subsequent biochemical marker measurement steps, diagnoses, and/or treatment recommendations specified by the AMI Reflex method according to such processing being output to display 70 and/or printer 72 .
  • digital computer system 60 may also have access to a patient database (e.g., stored on computer-readable medium 65 , or via a network to which computer system 60 has access) which includes other information to facilitate diagnosis or treatment.
  • the processor 66 executes the AMI Reflex algorithm in order to determine one or more biochemical marker measurements to be performed, and prompts an operator (e.g., via display 70 ) to execute the determined one or more biochemical marker measurements.
  • an immunoassay analyzer e.g., Immuno I, manufactured by Bayer Corporation
  • a clinical chemistry analyzer e.g., OpeRA, manufactured by Bayer Corporation
  • the operator inputs the results of the measurements for the patient into the processing system via, for example, the keyboard and/or mouse 68 .
  • the processing system specifies either an additional biochemical marker measurement(s) for execution or an indication of the patient's myocardial status (e.g., a diagnosis when the input is associated with the final biochemical marker measurement(s) of a measurement sequence).
  • the processing system may indicate suggested additional tests or treatments to be conducted and/or suggestions for clinically explaining the test results.
  • the processing system may, in addition to specifying subsequent biochemical marker tests to be executed for further titrating cardiac status, recommend certain treatments to mitigate further cardiac damage.
  • FIGS. 1A-1F may be implemented as a hierarchy of downwardly linked list of records, each record having associated fields which may contain elements relating to provisional or final indications (e.g., indications shown in the ellipses) and/or provisional or final recommended treatments to be output to display 70 and/or printer 72 , as well as pointers to other records in the list.
  • a main program and/or various subroutines or modules use the inputs to identify an appropriate pointer to point to the next record, and appropriate subroutines or modules handle processing and/or outputting any appropriate information from the fields.
  • the linked list may be further logically partitioned compared to the illustrative depiction in FIGS. 1A-1F such that indications and/or recommended treatments are more specifically dependent on the specific pathway traversed.
  • the program and/or linked list data may be stored in memory 64 (e.g., RAM) and processing unit 66 (CPU) processes these signals to effect the AMI Reflex algorithm.
  • a control processor 40 such as digital computer system 60 of FIG. 2 or a microcontroller or microprocessor with any associated elements (e.g., memory, etc.), may be interfaced, by way of well known interfacing techniques, or otherwise integrated, with an immunoassay analyzer 42 and a clinical chemistry analyzer 44 to control and/or acquire data from assay test equipment.
  • immunoassay analyzer 42 may be an Immuno I manufactured by Bayer Corporation
  • clinical chemistry analyzer 44 may be an OpeRA manufactured by Bayer Corporation, each interfaced to a personal computer or workstation which executes a program implementing the AMI Reflex algorithm (e.g., using PDC Concentrator software, from Technidata of France).
  • AMI Reflex algorithm e.g., using PDC Concentrator software, from Technidata of France.
  • the clinical chemistry analyzer and the immunoassay analyzer may run different samples (e.g., from different patients) concurrently in response to separate commands (e.g., writing into the respective loadlists of the analyzers) from processing system 40.
  • Sample transfer between immunoassay analyzer and clinical chemistry analyzer may be implemented by a sample load/exchange system 46 , which may be any of various known sample transfer mechanisms and systems (e.g., Labcell manufactured by Bayer, or LabInterlink manufactured by LabFrame of Omaha, Kansas), shown under the control of control processor 40 . It is understood that coupling of control processor 40 to sample load/exchange system 46 , immunoassay analyzer 42 , and clinical chemistry analyzer 44 may be implemented in various ways, such as dedicated buses or ports and/or shared buses or ports. Also, immunoassay analyzer 42 and clinical chemistry analyzer 44 may be operative in controlling sample exchange via sample load/exchange system 46 .
  • sample load/exchange system 46 may be any of various known sample transfer mechanisms and systems (e.g., Labcell manufactured by Bayer, or LabInterlink manufactured by LabFrame of Omaha, Kansas), shown under the control of control processor 40 . It is understood that coupling of control processor 40 to sample load/exchange system 46 , immunoassay analyze
  • various processor arrangements may be implemented to provide an immunoassay analyzer and a clinical chemistry analyzer which are coordinately controlled according to an AMI reflex algorithm in accordance with the present invention, such that all tests may be specified and automatically executed without human intervention, other than the ministerial task of drawing additional blood samples that may be required as requested by the processing system implementing the AMI Reflex algorithm.
  • the system of FIG. 3 may be implemented to closely integrate control processor 40 and the analyzers into a single instrument or platform, for example, by dedicating the control processor to the analysis equipment, each analyzer having its own processor.
  • a single processor e.g., control processor 40
  • the AMI Reflex algorithm may be executed cooperatively on only two processors, each dedicated to one of the analyzers, with a sample transfer system between the analyzers.
  • the immunoassay and clinical chemistry analyzers may have their own processors and be networked with one or more control processors or servers via a private network (e.g., a local area network (LAN), or a private wide area network (WAN)), or via a public network (e.g., Internet, WAN, or public-switched telephone network dial-up) to provide a public network-based Reflex algorithm service.
  • a private network e.g., a local area network (LAN), or a private wide area network (WAN)
  • a public network e.g., Internet, WAN, or public-switched telephone network dial-up
  • each analyzer may have its own, dedicated (e.g., local) processor, and a third control processor may coordinate overall processing according to the AMI Reflex method for the samples; such an implementation may employ various multiprocessing or parallel processing architectures or paradigms.
  • a master/slave implementation may be employed, with the third control processor being the master, the two local processors being slaves.
  • programmatic implementation of the Reflex algorithm may be distributed in various ways between control and each local processor.
  • the control processor may explicitly command each biochemical marker measurement for each analyzer in accordance with the AMI Reflex algorithm, and the local processors each controlling all the steps required to complete the specified measurement (e.g., sample and reagent handling, marker concentration measurement, etc.).
  • the respective local processors may be programmed to execute, in response to a single command or message from the control processor, subroutines or subsequences of the Reflex algorithm which include a series of measurement steps that are of the respective type measured on the analyzer (i.e., clinical chemistry assay or immunoassay), and the control processor may maintain overall coordination between the analyzers for branches between immunoassays and clinical chemistry assays for the various pathways of the AMI Reflex algorithm.
  • the local processor may communicate a message to the control processor (e.g., using an interrupt request) indicative of the branch point, and the control processor can appropriately communicate a message to the other analyzer as to which as to what measurement or subroutine should be executed on the sample (or take other appropriate action, such as provide a final diagnosis and treatment recommendations).
  • the control processor e.g., using an interrupt request
  • analyzers and control processors or servers may be coupled over a network.
  • the AMI Reflex method may be an application implemented by a server, and AMI Reflex method data may also be written into a patient database (e.g., directly from the automatic assay testing equipment).
  • an integrated automatic diagnostic combined immunoassay/clinical chemistry assay analyzer system may be implemented as a node on the network, and have access to other network resources such as patient databases.
  • Such a network implementation is well-suited for implementing an Expert system.
  • the AMI Reflex algorithm may be implemented according to various programming paradigms or data structures, some of which have been described by way of example for a particular implementation.
  • the program may be generally structured according to a hierarchical downward linked list of files.
  • the Reflex algorithm may be partitioned or distributed between or among dedicated processors for the immunoassay and clinical chemistry analyzers and a control processor in communication with the dedicated processors.
  • each of these systems may be implemented as Expert Systems.
  • the Reflex algorithm may be implemented to provide additional treatment or testing recommendations based on the specific progression of results along a measurement path (also referred to herein as sequence or thread).
  • the processing systems may also have access to additional patient data (e.g., via a database), such as patient medical history, family history, results from additional tests performed (e.g., electrocardiogram analysis) since admission, etc., and diagnosis and/or treatment recommendations may also account for such information.
  • additional patient data e.g., via a database
  • patient medical history e.g., patient medical history, family history
  • results from additional tests performed e.g., electrocardiogram analysis
  • diagnosis and/or treatment recommendations may also account for such information.
  • additional patient data e.g., via a database
  • patient medical history e.g., via a database
  • results from additional tests performed e.g., electrocardiogram analysis
  • diagnosis and/or treatment recommendations may also account for such information.
  • such an Expert system may be implemented off-line and/or on a network by a processor which is independent of the analyzers or control processor, and which has access to AMI Reflex method results and other patient data (e.g., coupled to a patient
  • a Reflex algorithm for AMI is only one of myriad possible reflex-type algorithms that may be developed for implementation by the foregoing illustrative systems which include both an immunochemistry analyzer and a clinical chemistry analyzer under control of at least one processor implementing a reflex-type algorithm.
  • a system may be employed to implement reflex-type algorithms that may be developed in order to diagnose other pathologies such as liver disease, lipid risk, or other pathologies where both immunoassays and clinical chemistry assays are used.
  • such a system may further integrate additional instrumentation to implement any further testing (e.g., hematology, urinalysis) required by the reflex algorithm.
  • the reflex algorithm in accordance with the present invention was evaluated and refined during a clinical trial at Hartford Hospital, Hartford, CT, in which it was demonstrated that performance of the algorithm can reduce the number of tests performed on a patient by about 70%, compared with a testing scheme in which all markers were tested regardless of the outcome of previous tests.
  • Other algorithms in the art suffer from the latter type of test scheme, which is more time consuming and costly than the novel reflex algorithm of the present invention.
  • the experiment comprised measurements of creatine kinase (tCK) activity, its MB isoenzyme (CKMB) as a mass assay, myoglobin, and cardiac troponin I (cTNI) for blood samples collected serially, upon admission and in four hour increments up through twelve hours post-admission, on patients presenting to the emergency room with a chief complaint of chest pain.
  • tCK creatine kinase
  • CKMB MB isoenzyme
  • cTNI cardiac troponin I
  • the cut-off (i.e., threshold) levels for Myoglobin, CKMB and Troponin I were used as recommended by the manufacturer of the test (i.e., Bayer in this case), and the cut-off level for t-CK was set at 100 U/L although the manufacturer recommends 130 U/L; this is to help to avoid false positive results during reflex testing.
  • the cut-off for the %RI (Percent Relative Index) was set at 4% For the purpose of this experimental study the data were run through the Reflex algorithm manually. It is noted that development of this illustrative Reflex algorithm considered the cost-effective use of cardiac markers for the emergency department evaluation of patients with chest pain.
  • endpoints A and B would require only the first sample at the time of admission; endpoints C, D, E and F would require only the first blood sample and an additional blood sample drawn 4 hours post-admission; endpoints G, H and I would require blood samples drawn up through 8 hours post-admission; endpoints J, K, L, M would require blood samples drawn through 12 hours post-admission; endpoints N, O and P would require blood samples drawn up through 16 hours post-admission; and endpoints Q and R would require blood samples drawn through 20 hours post-admission.
  • FIGS. 1A-1F The data thus clearly demonstrates that the illustrative Reflex algorithm of FIGS. 1A-1F according to the present invention is an efficient tool for proper utilization of cardiac markers in early detection of myocardial damage and can substantially reduce the cost by appropriate utilization of laboratory services.
  • a Reflex method according to the present invention not only helps determine the appropriate biochemical tests, but also eliminates unnecessary assays. Accordingly, it provides for a cost effective, unambiguous, and early diagnosis of acute myocardial infarctions and a stratification of risk for non-AMI patients, such as those with unstable angina pectoris.

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Claims (21)

  1. Computer-basiertes Verfahren zur Empfehlung einer Abfolge biochemischer Marker-Messtestverfahren, umfassend die Stufen, in denen man:
    eine Vielzahl von Abfolgen biochemischer Marker-Messstufen definiert, die als ein Entscheidungsbaum organisiert sind, wobei jede der genannten biochemischen Marker-Messstufen, die im genannten Entscheidungsbaum enthalten sind, einen biochemischen Test betrifft, mit dem ein Konzentrationsniveau oder eine Aktivität von mindestens einem biochemischen Marker eines myokardialen Infarkts in einer Serum-, Plasma- oder Vollblutprobe gemessen wird, worin jede Abfolge des genannten Entscheidungsbaums mit einer gemeinsamen ersten biochemischen Marker-Messstufe beginnt, die an einer ersten Serum-, Plasma- oder Vollblutprobe durchgeführt wird, wobei die genannte gemeinsame erste biochemische Marker-Messteststufe eine Vielzahl empfohlener Tests einschließt, mit denen eine Vielzahl biochemischer Marker mit unterschiedlicher Geschwindigkeit des Auftretens gemessen wird, jede der genannten biochemischen Marker-Messstufen im Anschluss an die genannte erste Stufe selektiv auf Basis der Ergebnisse aus einer vorhergehenden biochemischen Marker-Messstufe gemäß einem Reflex-Algorithmus durchgeführt wird, jede Abfolge in einer jeweiligen abschließenden biochemischen Marker-Messstufe endet, die an der Serum-, Plasma- oder Vollblutprobe durchgeführt wird, und wobei
    die Möglichkeit eines myokardialen Infarkts auf Basis der Ergebnisse der biochemischen Marker-Messstufen, die in die durchgeführte Abfolge eingeschlossen sind, und auf Basis der Ergebnisse der jeweiligen abschließenden biochemischen Marker-Messstufe indiziert wird.
  2. Verfahren gemäß Anspruch 1, worin in jeder der genannten biochemischen Marker-Messstufen mindestens ein biochemischer Marker gemessen wird, ausgewählt aus der Gruppe, bestehend aus Myoglobin, Gesamt-Creatin-Kinase, Creatin-Kinase-MB, Troponin T, Troponin I, Glycogen-Phosphorylase BB, Lactat-Dehydrogenase, Herz-Typ-Fettsäure-Bindungsprotein (h-FABP), Kohlensäure-Anhydrase III, Actin, Myosin und aus Creatin-Kinase MB-Isoformen.
  3. Verfahren gemäß Anspruch 1, worin die genannte gemeinsame erste biochemische Marker-Messstufe die Messung von Myoglobin und Gesamt-Creatin-Kinase einschließt.
  4. Verfahren gemäß Anspruch 3, worin die genannte gemeinsame erste biochemische Marker-Messstufe die Messung der Creatin-Kinase-Aktivität einschließt, und wobei im Fall eines Ergebnisses der Creatin-Kinase-Aktivität unterhalb einem vorbestimmten Niveau der nächste empfohlene Test in der Abfolge die Stufe umfasst, in der Myoglobin und Creatin-Kinase für die Serum-, Plasma- oder Vollblutprobe gemessen wird.
  5. Verfahren gemäß Anspruch 3, worin für die genannte gemeinsame erste biochemische Marker-Messstufe die Stufe eingeschlossen ist, in der die Creatin-Kinase-Aktivität gemessen wird, und wobei im Fall eines Ergebnisses der Creatin-Kinase-Aktivität oberhalb einem vorbestimmten Niveau der nächste empfohlene Test in der Abfolge die Stufe umfasst, in der Creatin-Kinase MB für die Serum-, Plasma- oder die Vollblut-Probe gemessen wird.
  6. Verfahren gemäß Anspruch 1, worin die genannten biochemischen Marker-Immunoassayverfahren und klinische Chemie-Assayverfahren einschließen.
  7. Verfahren gemäß Anspruch 1, worin die genannte Stufe zur Erstellung einer Indikation einschließt, dass der Zeitpunkt seit Einsetzen des Infarkts angezeigt wird.
  8. Verfahren gemäß Anspruch 1, worin einer oder mehrere Punkte entlang dem genannten Entscheidungsbaum eine empfohlene Behandlung oder einen Test anzeigen, der sich von dem biochemischen Marker-Messstufen innerhalb der Abfolgen des Entscheidungsbaums unterscheidet.
  9. Verfahren gemäß Anspruch 8, worin die empfohlene Behandlung oder der Test, der sich von den biochemischen Marker-Messungen unterscheidet, im Anschluss an eine oder mehrere der genannten jeweiligen abschließenden biochemischen Marker-Messstufen vorgesehen sind.
  10. Verfahren gemäß Anspruch 1, welches ferner eine Stufe einschließt, in der Steuerungssignale an zumindest ein automatisiertes Labor-Analysegerät in Entsprechung zu den genannten biochemischen Marker-Messstufen gesendet werden, die in der genannten Abfolge empfohlener Tests umfasst sind, um den Vollzug von zumindest einer der genannten biochemischen Marker-Messungen zu steuern.
  11. Verfahren gemäß Anspruch 10, worin das genannte mindestens eine automatisierte Labor-Analysegerät ein klinisches Chemie-Analysegerät oder ein Immunoassay-Analysegerät ist.
  12. Diagnostisches System, umfassend:
    ein Immunoassay-Analysegerät;
    ein klinisches Chemie-Analysegerät;
    ein Datenverarbeitungssystem, das an das genannte Immunoassay-Analysegerät und an das genannte klinische Chemie-Analysegerät gekoppelt ist, worin das genannte Datenverarbeitungssystem Mittel umfasst, die geeignet sind, alle Verfahrensstufen der Ansprüche 1 bis 11 durchzuführen.
  13. Diagnostisches System gemäß Anspruch 12, welches ferner ein Hämatologie-Analysegerät umfasst, das an das genannte Datenverarbeitungssystem gekoppelt ist, und worin das genannte Datenverarbeitungssystem ferner Mittel zur Steuerung des genannten Hämatologie-Analysegeräts umfasst, um zumindest eine der genannten biochemischen Marker-Messstufen aus der genannten Abfolge empfohlener Tests durchzuführen.
  14. Diagnostisches System gemäß Anspruch 13, worin das genannte Immunoassay-Analysegerät und das genannte klinische Chemie-Analysegerät jeweils örtliche Datenverarbeitungsmittel mit der Eignung zur Kommunikation mit dem genannten Datenverarbeitungssystem umfassen, und worin die genannten örtlichen Datenverarbeitungsmittel ferner Aufnahmemittel mit der Eignung zum Empfang von Kommandodaten aus dem genannten Datenverarbeitungssystem, welche die zu vollziehenden biochemischen Marker-Messstufentests betreffen, und Steuerungsmittel mit der Eignung zur Steuerung des Vollzugs der genannten biochemischen Marker-Messstufen umfassen, wie sie vom genannten Datenverarbeitungssystem spezifisch angegeben werden.
  15. Diagnostisches System gemäß Anspruch 13, worin das genannte Datenverarbeitungssystem ferner Aufnahmemittel mit der Eignung umfasst, aus dem genannten Immunoassay-Analysegerät und dem genannten klinischen Chemie-Analysegerät Daten zu empfangen, die Ergebnisse für die jeweiligen Tests betreffen, die vom genannten Immunoassay-Analysegerät und dem genannten klinischen Chemie-Analysegerät vollzogen werden.
  16. Diagnostisches System gemäß Anspruch 13, worin die genannten Datenverarbeitungsmittel ferner Speichermittel mit der Eignung umfassen, die genannten Daten, die Ergebnisse der jeweiligen Tests betreffen, die vom genannten Immunoassay-Analysegerät und dem genannten klinischen Chemie-Analysegerät vollzogen werden, in einer Patienten-Datenbasis in Kommunikation mit dem genannten Datenverarbeitungssystem zu speichern.
  17. Computer-Programm, ausgestaltet an einem Computer-lesbaren Medium, umfassend:
    Code-Mittel, die bei Vollzug an einer Maschine alle Verfahrensstufen der Ansprüche 1 bis 11 durchführen.
  18. Computer-Programm, ausgestaltet an einem Computer-lesbaren Medium gemäß Anspruch 17, welches ferner Code-Mittel umfasst, die bei Vollzug an einer Maschine die Verfahrensstufe zur Speicherung des genannten Entscheidungsbaums im genannten Computer-lesbaren Medium durchführt.
  19. Computer-Programm, ausgestaltet an einem Computer-lesbaren Medium gemäß Anspruch 17, welches ferner Code-Mittel umfasst, die bei Vollzug an einer Maschine die Verfahrensstufe zur Kommunikation mit dem genannten Immunoassay-Analysegerät und dem genannten klinischen Chemie-Analysegerät durchführt.
  20. Computer-Programm, ausgestaltet an einem Computer-lesbaren Medium gemäß Anspruch 19, welches ferner Code-Mittel umfasst, die bei Vollzug an einer Maschine die Verfahrensstufe zur Absendung von Kommandos an das genannte Immunoassay-Analysegerät und das genannte klinische Chemie-Analysegerät durchführen, um die genannten klinischen Marker-Messstufen zu vollziehen.
  21. Computer-Programm, ausgestaltet an einem Computer-lesbaren Medium gemäß Anspruch 19, welches ferner Code-Mittel umfasst, die bei Vollzug an einer Maschine die Verfahrensstufe zur Aufnahme der genannten Daten durchführen, die Ergebnisse aus den genannten Messungen betreffen, die vom genannten Immunoassay-Analysegerät und vom genannten klinischen Chemie-Analysegerät vollzogen werden.
EP99110216A 1998-06-02 1999-05-26 Reflexalgorithmus zur frühen und kostengünstigen Diagnose von myokardischen Infarkten geeignet für automatisierte diagnostische Plattformen Expired - Lifetime EP0962878B1 (de)

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PL333491A1 (en) 1999-12-06
US6099469A (en) 2000-08-08
AU2401399A (en) 1999-12-09
ATE232620T1 (de) 2003-02-15
EP0962878A2 (de) 1999-12-08
JP2000097936A (ja) 2000-04-07
EP0962878A3 (de) 2001-02-28
BR9905594A (pt) 2000-10-17
CA2270294A1 (en) 1999-12-02
DE69905310D1 (de) 2003-03-20
DE69905310T2 (de) 2003-10-16
NO992624D0 (no) 1999-06-01
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